Hepatitis C virus (HCV) often causes a prolonged and persistent infection, and an association between hepatocellular carcinoma (HCC) and HCV infection has been noted. HCV has evolved one or more strategies to suppress the host protective immune responses during acute infection; thereby facilitating the development ofviral persistence. We have identified a number of important functional properties of the HCV core protein. These include a trans-regulatory role on a number of cellular promoters, regulation of cell growth, an inhibitory role in programmed cell death (apoptosis) under certain conditions, and failure to induce a strong cytotoxic T lymphocyte response in immunized animals. While all of these functional activities are well established, there are critical gaps in our understanding of the mechanisms by which core protein exerts these functions. Together these observations provide a compelling reason to focus and design studies which will further our understanding of the cellular targets and molecular mechanisms associated with the functional effects of HCV core protein. This research proposal is designed to: (1) identify and characterize the core protein interacting cellular factors, (2) characterize the mechanism of core protein mediated apoptotic inhibition, and (3) determine the effect of core protein on MHC class II antigen expression. The core protein from HCV genotype la, one of the predominant genotypes seen in patients with chronic HCV infection in the United States, will be used in this study. The results from the proposed study will extend our understanding of the molecular mechanisms of core protein mediated functional activities and may lead to intervention strategies or the design of appropriate therapeutic modalities against HCV infection.